Feasibility study of gemcitabine plus docetaxel in advanced or recurrent uterine leiomyosarcoma and undifferentiated endometrial sarcoma in Japan

Takano, Tadao; Niikura, Hitoshi; Itō, Kiyoshi; Nagase, Satoru; Utsunomiya, Hiroki; Otsuki, Takeo; Toyoshima, Masafumi; Tokunaga, Hideki; Kaiho-Sakuma, Michiko; Shiga, Naomi; Nagai, Tatsuo; Tanaka, Sota; Otsuki, Ai; Kurosawa, Hiroki; Shigeta, Shogo; Tsuji, Kiichiro; Yamaguchi, Takuhiro; Yaegashi, Nobuo

doi:10.1007/s10147-013-0627-5

Cited by 21 publications

(10 citation statements)

References 37 publications

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“…3,27). Although results with GEM alone or in combination with DTX continue to be inconsistent between trials, it remains a standard second-line therapy for metastatic STS (28)(29)(30)(31)(32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

Arginine Starvation and Docetaxel Induce c-Myc–Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors

Prudner

Rathore

Robinson

et al. 2019

Clinical Cancer Research

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Purpose: The response to acute and long-term arginine starvation results in a conditional adaptive metabolic reprogramming that can be harnessed for therapeutic opportunities in ASS1-negative tumors. Here, we investigate the underlying biology of priming ASS1 À tumors with arginine deiminase (ADI-PEG20) before treatment with gemcitabine (GEM) and docetaxel (DTX) in sarcoma, pancreatic cancer, and melanoma cell lines.Experimental Design: ASS1 À tumor cell lines were treated to create LTAT (long-term ADI treated) cell lines (ASS1 þ ) and used for drug combination studies. Protein expression of ASS1, dCK, RRM2, E2F1, c-MYC, and hENT1 was measured. c-MYC activity was determined, live-cell immunofluorescent studies for hENT1, uptake assays of FITC-cytosine probe, and rescue studies with a c-MYC inhibitor were all determined in the presence or absence of the ADI-PEG20:GEM:DTX.Results: In examining modulations within the pyrimidine pathway, we identified that the addition of DTX to cells treated with ADI-PEG20 resulted in translocation of stabilized c-Myc to the nucleus. This resulted in an increase of hENT1 cell-surface expression and rendered the cells susceptible to GEM. In vivo studies demonstrate that the combination of ADI-PEG20:GEM: DTX was optimal for tumor growth inhibition, providing the preclinical mechanism and justification for the ongoing clinical trial of ADI-PEG20, GEM, and DTX in sarcoma.Conclusions: The priming of tumors with ADI-PEG20 and DTX results in the stabilization of c-MYC potentiating the effect of GEM treatment via an increase in hENT1 expression. This finding is applicable to ASS1-deficient cancers that are currently treated with GEM.

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Section: Introductionmentioning

confidence: 99%

Arginine Starvation and Docetaxel Induce c-Myc–Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors

Prudner

Rathore

Robinson

et al. 2019

Clinical Cancer Research

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“…The reason for this may be that our study included fewer patients with leiomyosarcoma, particularly of the uterus (n = 1), or undifferentiated pleomorphic sarcoma (n = 3), which might have a higher sensitivity to GD as shown in previous studies [11, 12, 19, 20]. In a phase II study reported by Pautier et al [19], RR was 24% in uterine leiomyosarcoma, but only 5% in other leiomyosarcomas.…”

Section: Discussionmentioning

confidence: 91%

“…Similarly, in a more recent French randomized phase II study, the RR was higher for leiomyosarcoma of uterus than for leiomyosarcoma of other organs (24% vs. 5%) [19]. A small Japanese phase II study reported that a response was observed in three of eight (38%) patients with uterine leiomyosarcoma [20]. Despite the lack of phase III studies, these phase II studies suggest that GD is a promising regimen in soft-tissue sarcoma, possibly particularly in uterine leiomyosarcoma, at least as second- or later-line therapy.…”

Section: Introductionmentioning

confidence: 95%

Efficacy and safety of gemcitabine plus docetaxel in Japanese patients with unresectable or recurrent bone and soft tissue sarcoma: Results from a single-institutional analysis

et al. 2017

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BackgroundCombination therapy with gemcitabine and docetaxel has been reported to be a good therapeutic strategy for patients with soft tissue sarcoma. The aim of the present study was to analyze the efficacy and toxicity of gemcitabine with docetaxel in Japanese patients with advanced bone and soft tissue sarcoma.Patients and methodsWe retrospectively analyzed the effect of gemcitabine and docetaxel therapy on overall response, progression-free survival, overall survival, and toxicity in 42 patients with bone or soft tissue sarcoma who had received the therapy between October 2006 and September 2015, at Tohoku University Hospital.ResultsThe median age was 55 years; 23 patients were men, and 19 were women. Eight had bone sarcoma and 34 had soft tissue sarcoma. Forty patients (95%) had previously been treated with one or more chemotherapeutic regimens. The overall response rate was 6.9% and the disease control rate was 55%. The median progression-free survival was 2.3 months and the median overall survival was 14.3 months. Grade 3 or more neutropenia and febrile neutropenia were observed in 74% and 4.8% of all patients, respectively.ConclusionThe response rate was lower and myelosuppression was more frequently observed than in other previous reports. On the other hand, most of toxicities were enough manageable. In addition, some patients had long survival with a good response. Our study supports the notion that gemcitabine and docetaxel therapy is a good therapeutic option for treating patients with advanced soft tissue sarcoma as well as bone sarcoma, also in Asian populations.

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“…Combination therapy of gemcitabine and docetaxel has been a standard regimen of chemotherapy according to results of phase II trials [15][16][17], and there have been favorable results from a phase II trial (SARC 005) regarding adjuvant treatment with docetaxel and gemcitabine followed by doxorubicin in patients with uterus-limited ULMS [18]. However, our previous report revealed that dose reduction due to bone marrow suppression was frequently required with docetaxel and gemcitabine therapy, especially in Japanese patients [19]. According to the results of previous studies, clinical features of ULMS were although FIGO stage was distributed early stage, but exhibited a poor prognosis (Table 3).…”

Section: Discussionmentioning

confidence: 94%

Current Status of Uterine Leiomyosarcoma in the Tohoku Region: Results of the Tohoku Translational Center Development Network Survey

et al. 2017

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Feasibility study of gemcitabine plus docetaxel in advanced or recurrent uterine leiomyosarcoma and undifferentiated endometrial sarcoma in Japan

Abstract: The gemcitabine plus docetaxel regimen without prophylactic G-CSF support was tolerable and highly efficacious in Japanese patients with advanced or recurrent LMS and UES.

Cited by 21 publications

References 37 publications

Arginine Starvation and Docetaxel Induce c-Myc–Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors

Arginine Starvation and Docetaxel Induce c-Myc–Driven hENT1 Surface Expression to Overcome Gemcitabine Resistance in ASS1-Negative Tumors

Efficacy and safety of gemcitabine plus docetaxel in Japanese patients with unresectable or recurrent bone and soft tissue sarcoma: Results from a single-institutional analysis

Current Status of Uterine Leiomyosarcoma in the Tohoku Region: Results of the Tohoku Translational Center Development Network Survey

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